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Methods of enhancing diabetes resolution
8710002 Methods of enhancing diabetes resolution
Patent Drawings:

Inventor: Rothkopf
Date Issued: April 29, 2014
Application:
Filed:
Inventors:
Assignee:
Primary Examiner: Wax; Robert A
Assistant Examiner: Craigo; William
Attorney Or Agent: Lerner, David, Littenberg, Krumholz & Mentlik, LLP
U.S. Class: 514/7.2; 514/249; 514/412; 514/423; 514/6.9
Field Of Search:
International Class: A61K 38/26; A61K 38/22; A61K 31/4985; A61K 31/40; A61K 31/403; A61P 3/10
U.S Patent Documents:
Foreign Patent Documents: WO 2005082928; WO 2006000567; WO 2006086769; 2008/087190
Other References: Morinigo, Obesity Surgery, 16, 2003. cited by examiner.
Dolan, Obesity Surgery, 13, 2003. cited by examiner.
Drucker, Lancet, 368, 2006. cited by examiner.
Kubota, the Journal of Biological Chemistry, 2003. cited by examiner.
International Search Report, PCT/US2008/013122, dated Mar. 6, 2009. cited by applicant.
Rothkopf Michael M et al: Surgery for Obesity and Related Diseases : Official Journal of the American Society for Bariatric Surgery, 5(1); 128-131 (2000). cited by applicant.
Fetner H et al: Surgery for Obesity and Related Diseases. Else Vieh, NL, 1(6); 589-597 (2005). cited by applicant.
Korner et al: Surgery for Obesity and Related Diseases, Elsevier, NL, 3(6); 597-601 (2007). cited by applicant.
Korner J et al:Surgery for Obesity and Reiated Diseases, Elsevier, NL, 1(3); 222 (2005). cited by applicant.
Guidone Caterina et al: Diabetes, 55(7); 2025-2031 (2006). cited by applicant.
Strader et al: Physiology and Behavior. Elsevier Science Ltd., Oxford, GB, 88(3); (2006). cited by applicant.
Frezza Ermenegildo Eldo: Obesity Surgery 14(7); 999-1005 (2004). cited by applicant.
Mingrone et al: NMCD. Nutrition Metabolism and Cardiovascular Diseases, Milan, IT, 18(8); 574-579 (2008). cited by applicant.
Bose Mousumi et al: Obesity Surgery, 19(2); 217-229 (2009). cited by applicant.
Rodieux Frederique et al: Obesity (Silver Spring, MD.) 16(2); 298-306 (2008). cited by applicant.









Abstract: Disclosed are compositions and methods for increasing diabetes resolution in a diabetic patient having undergone gastric restrictive surgery, entailing use of active agent that produces an incretin-like effect in the patient.
Claim: The invention claimed is:

1. A method for achieving diabetes resolution in a type II diabetic patient having undergone gastric restrictive surgery that does not involve a bypass, comprisingadministering to the patient an agent that produces an incretin-like effect in the patient in an amount effective to achieve diabetes resolution, wherein the agent comprises glucagon-like peptide 1 (GLP-1), or an analog or derivative of GLP-1.

2. The method of claim 1, wherein the agent comprises exendin-4.

3. The method of claim 2, wherein exendin-4 is administered in a daily dosage of about 5 to about 30 micrograms.

4. The method of claim 2, wherein exendin-4 is administered in a daily dosage of about 10 micrograms.

5. The method of claim 3, wherein said daily dosage comprises two divided doses.

6. The method of claim 4, wherein said daily dosage comprises about 20 micrograms.

7. The method of claim 2, wherein the patient is administered exendin-4 in a first daily dosage of about 10 micrograms, wherein said first daily dosage is administered for about 1 month, and wherein said patient is then administered exendin-4in a second daily dosage of about 20 micrograms.

8. The method of claim 7, wherein said second daily dosage is continued for at least one month.

9. The method of claim 8, wherein said second daily dosage is continued for at least 6 months.

10. The method of claim 8, wherein said second daily dosage is continued for at least 12 months.

11. The method of claim 1, wherein the patient is administered at least one additional agent that produces an incretin-like effect in the patient.

12. The method of claim 11, wherein said additional agent comprises GIP-1 or an analog or derivative thereof.

13. The method of claim 11, wherein said additional agent comprises sitagliptin.

14. The method of claim 1, wherein the gastric restriction surgery undergone by the patient comprises adjustable gastric binding, vertical banded gastroplasty, gastric stapling, gastric partitioning, or gastric plication.

15. The method of claim 1, wherein the GLP-1 analog is Exendin-3.

16. The method of claim 1, wherein the GLP-1 derivative is liraglutide.
Description: SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Feb. 17, 2014, is named MROTH3.3-001_SL.txt, and is 23,735 bytes insize.

BACKGROUND OF THE INVENTION

Obesity is has become a health concern of global proportion. The National Center for Health Statistics (NCHS) estimates that over 120 million Americans are overweight, including about 56% of the adult population. Of these, about 52 million areconsidered obese, as measured by a body mass index (BMI) of 30% or greater. In Europe, an estimated 77 million people are obese, as measured by the same standard. This problem is not limited to western nations, as many developing countries are reportedto have obesity rates over 75% of the adult population.

Type II Diabetes is a significant factor in the obese. Type II diabetes is characterized by a gradual loss of insulin secretion and a progressive reduction in .beta.-cell mass. Insulin resistance increases the demand for insulin. As the.beta.-cell mass declines, the pancreas is unable to sustain the high insulin levels required to maintain normoglycemia.

Weight loss, diet alteration and exercise can improve glycemic control. Beyond these measures, medical therapy of diabetes is intended to control blood sugar within acceptable limits. Patients with diabetes have a wide a number of therapeuticapproaches. Medications such as sulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors are available orally. Insulin can be injected or inhaled. Recently a new class of drugs, labeled incretin-mimetics, aimed at enhancing theincretin effect, has been introduced. Many of these drugs, e.g., exenatide, require injection. As effective as they are, however, patients with diabetes can be expected to remain on diabetic medications for their entire lives.

Surgical options exist for obese diabetics, including relatively invasive surgeries such as gastric bypass surgery and duodenal switch surgery, and less invasive surgeries referred to as gastric restriction surgeries. In both gastric bypass andduodenal switch surgery, the capacity of the stomach is significantly reduced and a portion of the small intestine is rerouted. However, the degree of malabsorption is greater in duodenal switch surgery than gastric bypass surgery. Gastric restrictionsurgeries differ from bypass techniques in that the stomach capacity is reduced but the intestine is left substantially intact.

Diabetes resolution occurs in 48-95% of post-surgical patients, depending on the specific surgery. Thus surgery offers the potential of achieving complete resolution of type II diabetes. This enables patients to stop diabetic medications andglucose self-monitoring entirely.

Gastric bypass procedures (RYGB) incur a great deal of morbidity and create a malabsorptive state in the patient by passing a large portion of the intestines. Diabetes resolution (dR) has been reported to occur in 84% of patients after gastricbypass surgery. Cummings, et al., Surgery for Obesity and Related Diseases 3:109-15 (2007).

Gastrointestinal sleeves have been implanted to line the stomach and/or a portion of the small intestines to reduce the absorptive capabilities of the small intestine and/or to reduce the volume in the stomach, by reducing the available volumeto the tubular structure of the graft running there through. Although weight loss may be effective while these types of devices are properly functioning, there are complications with anchoring the device within the stomach/GI tract, as the stomach andGI tract function to break down things that enter into them and to move/transport them through. Accordingly, the integrity of the anchoring of the device, as well as the device itself may be compromised over time by the acids and actions of the stomachand GI tract.

A sleeve gastrectomy is an operation in which the left side of the stomach is surgically removed. This results in a much reduced stomach which is substantially tubular and may take on the shape of a banana. This procedure is associated with ahigh degree of morbidity, as a large portion of the stomach is surgically removed. Additionally, there are risks of complications such as dehiscence of the staple line where the staples are installed to close the surgical incisions where the portion ofthe stomach was removed. Further, the procedure is not reversible.

In the laparoscopic duodenal switch (also referred to as biliopancreatic diversion or BPD), the size of the stomach is reduced in similar manner to that performed in a sleeve gastrectomy. Additionally, approximately half of the small intestineis bypassed and the stomach is reconnected to the shortened small intestine. This procedure suffers from the same complications as the sleeve gastrectomy, and even greater morbidity is associated with this procedure due to the additional intestinalbypass that needs to be performed. Still further, complications associated with malabsorption may also present themselves. Diabetes resolution has been reported to occur in 95% of patients after duodenal switch surgery (BPD). This diabetes resolutionmay occur within days after RYGB and BPD, often even before significant weight loss has occurred.

Gastric reduction or restrictive techniques have also been attempted. Unlike bypass procedures, these techniques do not involve reduction of intestinal volume. Such reduction or restrictive techniques include inserting instruments trans-orallyand reducing the volume of the stomach by stapling portions of it together. The LAPBAND.TM. is a band that, when placed, encircles the fundus-cardia junction and is inflatable to constrict the same. It does not reduce the volume of the stomach, butrather restricts passage of food into the stomach, the theory being that the patient will feel satiety with a much less volume of food than previously. Diabetes resolution has been reported to occur in only 48% of patients after gastric restrictionsurgery, such as adjustable gastric binding (i.e., the LAPBAND.TM.). Cummings, et al., Surgery for Obesity and Related Diseases 3:109-15 (2007).

SUMMARY OF THE INVENTION

An aspect of the present invention is directed to a method for increasing diabetes resolution in a type II diabetic patient having undergone gastric restrictive surgery comprising administering to the patient an agent that produces or causes anincretin-like effect in the patient, in an amount effective to achieve diabetes resolution. In some embodiments, the agent is an incretin hormone such as glucagon-like peptide 1 (GLP-1), gastric inhibitory protein (GIP), or an analog or derivativethereof of GLP-1 or GIP. In some other embodiments, the agent is not an incretin hormone, per se, but acts to increase endogenous incretin hormone activity level, such as by inhibiting degradation of endogenous incretin hormones. In some embodiments,the agent is a DPP IV inhibitor.

The present invention increases diabetic resolution in type II diabetic patients after gastric restriction surgery, thus allowing them to discontinue treatment and medication for diabetes indefinitely or even permanently, and may also improveweight loss outcomes.

DETAILED DESCRIPTION

As used herein, diabetes resolution generally refers to the restoration of normal glucose metabolism, the presence of which can be determined by standard techniques in the art as described and/or referenced herein. The term "administer" (oradministered or administering) as used herein includes administration by the patient him/herself.

As used herein, gastric restriction surgery refers to surgeries in which the stomach is altered in a manner that restricts the normal passage of food, leading to a reduction in food intake. This can be accomplished by a reduction in the overallstomach size, a reduction in the gastric capacity or a change in the stomach configuration. Gastric restriction surgery differs from RYGB and BPD because it does not involve a bypass (and thus reduction) of the small intestine. As a result, gastricrestriction surgery does not increase the output of gastrointestinal hormones from the K and L cells. Exemplary illustrations of gastric restriction surgeries include LAPBAND.TM. surgery (adjustable gastric binding) and vertical banded gastroplasty. Other illustrations of gastric restriction surgeries include gastric stapling, gastric partitioning and gastric plication.

Diabetes Mellitus exists in two forms, type I and type II. Type I diabetics have a severe deficiency of insulin production from the .beta.-cells of the pancreatic islets. Their endogenous insulin production is very, very low, and thusinadequate to regulate blood glucose levels. They require injections of insulin to keep their blood glucose normalized and to prevent keto-acidosis. In contrast, type II diabetes is characterized by insulin resistance, which means that additionalamounts of insulin must be produced to achieve the same decrease in blood glucose. Insulin resistance generally refers to a condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and livercells. Insulin resistance in fat cells results in hydrolysis of stored triglycerides, which elevates free fatty acids in the blood plasma. Insulin resistance in muscle reduces glucose uptake, whereas insulin resistance in liver reduces glucose storage,with both effects serving to elevate blood glucose.

Over time, the disease progress to a point where pancreatic cell production of insulin fails to keep up with the body's demand, resulting in an increasingly wide gap between the body's requirements for insulin and its own insulin production. Insulin resistance can be caused by many different kinds of factors, including obesity, medication and genetic factors. Thus, type II diabetics make insulin sufficient to prevent ketoacidosis but not enough to meet the heightened requirements of theirinsulin-resistant state. Accordingly, treatment of type II diabetes is intended to control three factors, namely glucose delivery, insulin resistance and insulin production.

Without intending to be found by theory, Applicant hypothesizes that the wide difference in diabetes resolution observed between gastric restriction surgery, which has been reported to be about 48%, and the intestinal bypass or diversionprocedures, which has been reported to be about 84%, is due to intestinal factors, and that increased gastrointestinal hormone secretion and particularly incretin hormone secretion, creates a metabolic influence in favor of diabetes resolution after RYGBand BPD. The gastric restriction surgery reduces food intake and therefore lowers glucose delivery. The weight loss that typically results from gastric restriction surgery reduces insulin resistance. Therefore, the present inventor hypothesizes thatthe difference observed in diabetes resolution between gastric restriction surgery and RYGB is most likely due to the lack of increased intestinal hormone secretion after gastric restriction surgery. In other words, both types of surgery achieve controlof glucose intake because they cause the patient to ingest less food, albeit in very different ways. However, the increased hormone secretion observed after RGYB corrects the imbalance between insulin resistance and insulin production, and achieves arestoration of normal glucose metabolism and blood levels.

The present invention, therefore, addresses each of these three factors. The invention makes further use of agents with incretin-like activity or which produce or cause an incretin-like effect, which for purposes of the present invention,includes decreased glucose delivery (e.g., appetite reduction, increased satiety and/or slowed gastric emptying), reduced insulin resistance and increased insulin production. Basically, the patient may experience a restoration of normal incretinresponse to glucose challenge or a supra-normal incretin response to glucose challenge. The combination of this therapeutic intervention not only enhances the effects of gastric restriction surgery by lowering glucose delivery (resulting in lower, e.g.,normal, levels of fasting blood or serum glucose) and reducing insulin resistance, but these agents also go further by increasing insulin production. Thus, the combination of gastric restriction surgery and agents with incretin-like activity increasediabetes resolution beyond the 48% reported in the literature as achievable with gastric restriction surgery alone. In some embodiments, the increases diabetes resolution may be as high as 80% or better.

Diabetic patients for whom gastric restriction surgery is recommended tend to be obese. Unless stated otherwise in connection with any specific embodiments disclosed herein, treatment with the agent(s) of the present invention may begin anytime after gastric restriction surgery, but usually about 3 months thereafter. By this time, it is more probable that diabetes resolution will have occurred without therapeutic intervention. Timing of the administration is not critical, but isdesirably within 1 hour of a meal. Although the time course of the hormone therapy may vary for each patient, the duration of treatment generally ranges from about 1 to about 24 months.

When diabetes resolution occurs after gastric restriction surgery (e.g., LAPBAND.TM.), it usually takes several months and often requires weight loss. Thus, there is a fundamental difference in diabetes resolution in gastric restriction surgerycompared to more invasive forms of bariatric surgery to treat obesity. Active agents suitable for use in the present invention include incretin hormones, per se, (including both natural and synthetic versions thereof), analogs, derivatives and mimeticsof such hormones, and agents that increase endogenous activity levels of incretin hormones.

Incretin hormones suitable for use in the present methods are recognized to play an important role in food intake, weight loss and glyceric response. These include GLP-1 (glucagon like peptide-1) and GIP (gastric inhibitory peptide, also knownas glucose-dependent insulinotropic polypeptide). Together with autonomic nerves they play a vital supporting role to the pancreatic islets in the control of blood glucose homeostasis and nutrient metabolism.

Human GLP-1 is a 37-amino acid peptide (SEQ ID NO: 1) originating from preproglucagon, which is synthesized for example, in the L-cells in the distal ileum, in the pancreas and in the brain, and then further processed into shorter peptide(s),e.g., GLP-1 (7-36)amide (SEQ ID NO: 2). GLP-1 is normally secreted in response to food intake in particular carbohydrates and lipids stimulate GLP-1 secretion. GLP-1 has been identified as a very potent and efficacious stimulator for insulin release. GLP-1 has been reported to lower plasma glucagon concentrations, slow gastric emptying, stimulate insulin biosynthesis, enhance insulin sensitivity, and enhance the ability of the B-cells to sense and respond to glucose in subjects with impaired glucosetolerance. The insulinotropic effect of GLP-1 in humans has been reported to increase the rate of glucose metabolism partly due to increased insulin levels and partly due to enhanced insulin sensitivity. Other studies have shown that infusions ofslightly supra-physiological amounts of GLP-1 significantly enhance satiety and reduce food intake in normal subjects, and that the effect on food intake and satiety is preserved in obese subjects.

As used herein, a "GLP-1 analog" refers to a molecule having a modification including one or more amino acid substitutions, deletions (e.g., fragments), inversions, or additions when compared with GLP-1. A useful GLP-1 analog is GLP-1(7-37),which is represented by the sequence: NH.sub.2-His.sup.7-Ala -Glu-Gly.sup.10-Thr-Phe-Thr-Ser-Asp.sup.15-Val-Ser-Ser-Tyr-Lee.sup.20-Glu- -Gly-Gln -Ala-Ala.sup.25-Lys-Glu-Phe-Ile-Ala.sup.30-Trp-Leu-Val-Lys-Gly.su- p.35-Arg-Gly.sup.37-COOH (SEQ ID NO: 3). Other GLP-1 analogs known in the art and that may be useful in the practice of the present invention include, for example, GLP-1(7-34) (SEQ ID NO: 4) and GLP-1(7-35) (SEQ ID NO: 5), GLP-1(7-36) (SEQ ID NO: 6), Val.sup.8-GLP-1(7-37) (SEQ ID NO: 7),Gln.sup.9-GLP-1(7-37) (SEQ ID NO: 8), D-Gln.sup.9-GLP-1(7-37) (SEQ ID NO: 57), Thr.sup.16-Lys.sup.18-GLP-1(7-37) (SEQ ID NO: 9), and Lys.sup.18-GLP-1(7-37) (SEQ ID NO: 10), among which include biologically processed versions of full-length GLP-1.

Yet other suitable GLP-1 analogs include exendins (see, e.g., U.S. Patent Application Publication 20060189520), which are peptides that are found in the venom of the Gila-monster, a lizard found in Arizona, and the Mexican Beaded Lizard. Exendin-3 is present in the venom of Heloderma horridum, and exendin-4 is present in the venom of Heloderma suspectum. The exendins have some sequence similarity to several members of the glucagon-like peptide family, with the highest homology, 53%,being to GLP-1[7-36]NH.sub.2 (SEQ ID NO: 11) (Goke, et al., J. Biol. Chem. 268:19650-55 (1993)). Like GLP-1 (SEQ ID NO: 1), exendins have also been reported to inhibit gastric emptying.

Exendins suitable for use in the present invention include exendin-3 (which is represented by the amino acid sequence: His Ser Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer Ser Gly Ala Pro Pro Pro Ser] (SEQ ID NO: 12), and exendin-4 (which is represented by the amino acid sequence: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly AlaPro Pro Pro Ser] (SEQ ID NO: 13), and other compounds, called exendin agonists, which effectively bind to the receptor at which exendin exerts its action on reducing food intake. Representative exendin agonists include exendin-4 (1-30) (SEQ ID NO: 14),exendin-4 (1-30) amide (SEQ ID NO: 15), exendin-4 (1-28) amide (SEQ ID NO: 16), .sup.14Leu, .sup.25Phe exendin-4 amide (SEQ ID NO: 17), .sup.14Leu, .sup.25Phe exendin-4 (1-28) amide (SEQ ID NO: 18), and .sup.14Leu, .sup.22Ala, .sup.25Phe exendin-4 (1-28)amide (SEQ ID NO: 19). Exendins and exendin agonists that may be useful in the present invention are disclosed in U.S. Patent Application Publication Nos. 2003/0087821, 2005/0101537 and 2005/0043238.

Exendin compositions useful in the invention may conveniently be provided in the form of formulations suitable for parenteral (including intravenous, intramuscular and subcutaneous) or nasal or oral administration.

As used herein, a "GLP-1 derivative" refers to a molecule having the amino acid sequence of GLP-1 or of a GLP-1 analog, but additionally having at least one chemical modification of one or more of its amino acid side groups, a-carbon atoms,terminal amino group, (e.g., GLP-1 (7-36)amide (SEQ ID NO: 2)) or terminal carboxylic acid group. A chemical modification includes adding chemical moieties, creating new bonds, and removing chemical moieties. Modifications at amino acid side groupsinclude acylation of lysine .epsilon.-amino groups, N-alkylation of arginine, histidine, or lysine, alkylation of glutamic or aspartic carboxylic acid groups, and deamidation of glutamine or asparagine. Modifications of the terminal amino include thedes-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications. Modifications of the terminal carboxy group include the amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications. A lower alkyl is a C.sub.1-C.sub.4 alkyl. Furthermore, one or more side groups, or terminal groups, may be protected by protective groups known to the ordinarily-skilled protein chemist. The .alpha.-carbon of an amino acid may be mono-methylated or di-methylated. See, e.g., U.S. PatentApplication Publication 2004/0018975, and U.S. Pat. Nos. 5,118,666 and 5,545,618. Among the GLP-1 analogs and derivatives taught in U.S. Pat. No. 5,545,618 include those which have amino acid substitutions as positions 7-10 and/or are truncated atthe C-terminus and/or contain various other amino acid substitutions in the basic peptide. Analogs and derivatives having D-amino acid substitutions in the 7 and 8 positions and/or N-alkylated or N-acylated amino acids in the 7 position are disclosedtherein as being particularly resistant to degradation in vivo. Liraglutide (Arg.sup.34, Lys.sup.26(N.sup..epsilon.-(.gamma.-Glu(N.sup..alpha.-hexadecanoyl)))-GLP- -1(7-37)) (SEQ ID NO: 20) is yet another GLP-1 derivative that may be useful in thepresent invention. Also known as NN2211, liraglutide is a long acting GLP-1 derivative that is obtained by acylation of the GLP-1 molecule, which upon entering the bloodstream, is extensively bound to albumin which protects it from degradation by DPP-IVand reduces renal clearance. See, Elbrond, et al., Diabetes Care 25(8):1398-404 (2002); and Madsbad, et al., Diabetes Care 27:1335-42 (2004) (and various references cited therein, including Knudsen, et al., Drugs of the Future 26:677-85 (2001)). Asdisclosed in Madsband, liraglutide may be administered via i.v. injection, once-a-day, for about 3 months, or even longer at fixed dosages of from 0.045-0.75 mg, or higher. It is available commercially from Novo Nordisk, Denmark.

GIP is released from intestinal endocrine K-cells into the bloodstream following ingestion of carbohydrate, protein and particularly fat. GIP's major physiological role is now generally believed to be that of an incretin hormone that targetspancreatic islets, and like GLP-1, enhances insulin secretion. (Creutzfeldt, W., Exp. Clin. Endocrinol. Diabetes 109:S288-S303 (2001)). GIP also helps reduce postprandial hyperglycemia. Id. GIP acts through binding to specific G-protein coupled GIPreceptors located on pancreatic beta-cells (Wheeler, et al., Endocrinology 136:4629-39 (1995)).

Naturally occurring GIP (also referred to as native GIP) is a 42-amino acid peptide hormone, having the (human) sequence Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys GlyLys Lys Asn Asp Trp Lys His Asn Ile Thr Gln (SEQ ID NO: 21). GIP antagonists that are relatively resistant to degradation by DPP IV are also useful in the present invention. Such antagonists, also referred to as peptide analogues of GIP(1-42), includeGIP(1-12) (SEQ ID NO: 22), GIP(1-13) (SEQ ID NO: 23), GIP(1-14) (SEQ ID NO: 24), GIP(1-15) (SEQ ID NO: 25), GIP(1-16) (SEQ ID NO: 26), GIP(1-17) (SEQ ID NO: 27), GIP(1-18) (SEQ ID NO: 28), GIP(1-19) (SEQ ID NO: 29), GIP(1-20) (SEQ ID NO: 30), GIP(1-21)(SEQ ID NO: 31), GIP(1-22) (SEQ ID NO: 32), GIP(1-23) (SEQ ID NO: 33), GIP(1-24) (SEQ ID NO: 34), GIP(1-25) (SEQ ID NO: 35), GIP(1-26) (SEQ ID NO: 36), GIP(1-27) (SEQ ID NO: 37), GIP(1-28) (SEQ ID NO: 38), GIP(1-29) (SEQ ID NO: 39), GIP(1-30) (SEQ ID NO:40), GIP(1-31) (SEQ ID NO: 41), GIP(1-32) (SEQ ID NO: 42), GIP(1-33) (SEQ ID NO: 43), GIP(1-34) (SEQ ID NO: 44), GIP(1-35) (SEQ ID NO: 45), GIP(1-36) (SEQ ID NO: 46), GIP(1-37) (SEQ ID NO: 47), GIP(1-38) (SEQ ID NO: 48), GIP(1-39) (SEQ ID NO: 49),GIP(1-40) (SEQ ID NO: 50), GIP(1-41) (SEQ ID NO: 51) and GIP(1-42) (SEQ ID NO: 21), where the base peptide possesses one or more of the following modifications: (1) an amino acid substitution at Glu.sup.3, e.g., proline, hydroxyproline, lysine, tyrosine,phenylalanine or tryptophan; (2) a modification by fatty acid addition e.g., a C-8, C-10, C-12, C-14, C-16, C-18 or a C-20 palmitate (PAL) group to an epsilon amino group of at least one lysine residue e.g., Lys.sup.16 or Lys.sup.37, which have beenreported to circumvent the problem of renal filtration; and (3) a modification by N-terminal acetylation. See, e.g., U.S. Patent Application Publication 2007/0167370. Although literature categorizes all three categories as GIP-1 antagonists oranalogs, consistent with usage of terminology in the present invention, the modified GIP-1 proteins in the first category are referred to as GIP-1 analogs, and the modified GIP proteins in the latter two categories are referred to as GIP-1 derivatives. Thus, specific representative GIP analogs and derivatives include N-AcGIP (1-42) (SEQ ID NO: 52), GIP(1-42)(Lys.sup.37PAL) (SEQ ID NO: 53), N-AcGIP(1-42)(Lys.sup.16PAL) (SEQ ID NO: 54) and N-AcGIP(1-42)(Lys.sup.37PAL) (SEQ ID NO: 55). Further analogsare disclosed in U.S. Patent Application Publication Nos. 20020151495, 20030232761 and 2007/0167363 (e.g., GIP (7-30) (SEQ ID NO: 56)).

Administration of GIP or its analogs or derivatives of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as by oralingestion, inhalation, topical application or cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection.

Dipeptidyl peptidase IV (DPP-IV) inhibitors refer to compounds that inhibit activity of DPP-IV, a membrane-associated amino peptidase of 766 amino acids that acts preferentially on substrates with an amino-terminal proline or alanine at position2, such as GLP-1, GLP-2, and GIP. Inhibitors of DPP-IV have been shown to increase circulating levels of GLP-1 and GIP; thus, they may show an enhanced effect on diabetes resolution for purposes of the present invention. Suitable DPP-IV inhibitorsinclude sitagliptin ((R)-3-Amino-1-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]-p- yrazin-7-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one, described in WO03/004498, and commercially available from Merck & Co.), vildagliptin (pyrrolidine,1-[(3-hydroxy-1-adamantyl)amino]acetyl-2cyano-, (S), or (S)-1-[2-((5S,7S)-3-Hydroxy-adamantan-1-ylamino)-acetyl]-pyrrolidine-2-ca- rbonitrile, described in WO00/034241, and commercially available from Novartis), and saxagliptin((1S,3S,5S)-2-[(S)-2-amino-2-(3-hydroxy-adamantan-1-yl)-acetyl]-2-aza-bic- yclo[3.1.0]hexane-3-carbonitrile, described in WO01/68603). In addition to these compounds, other DPP IV inhibitors that may be useful in practicing the present invention aredescribed in U.S. Patent Application Publication 2007/0098781 (and publications referenced therein). DPP-IV inhibitors are typically administered orally.

The agents of the present invention may be prepared in accordance with standard techniques, disclosed for example in the literature cited herein, including (particularly with respect to the peptide-based agents) solid-phase synthetic chemistryand recombinant DNA technology (with respect to the amino acid portion of the product), coupled with subsequent chemical modification, enzymatic modification and combinations thereof.

The agents may be administered in the form of pharmaceutically acceptable salts, e.g., acid-addition salts and basic-addition salts. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such, as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid,and the like. Examples of such salts include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate,caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate, and the like. Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing thesalts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like. Unless already present in a derivative of the agent, the agents may also be administered in the form of a pharmaceuticallylower alkyl ester or amide.

Administration of the agents of the present invention may be via any route known to be safe and effective by the physician of ordinary skill in the art. When a therapeutically effective amount of the composition of the present invention isadministered orally, the composition of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solidcarrier such as a gelatin or an adjuvant. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. Theliquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. Controlled release preparations may beachieved by the use of polymers to complex or absorb the active compound used in the present invention. Extended duration may be obtained by selecting appropriate macromolecules, for example, polyesters, polyamino acids, polyvinylpyrrolidone,ethylene/vinyl acetate, methylcellulose, carboxymethylcellulose, or protamine sulfate, and by selecting the concentration of macromolecules, as well as the methods of incorporation, in order to prolong release. Such teachings are known to those of skillin the art and disclosed, e.g., in Remington's Pharmaceutical Sciences, 1980.

In other embodiments, delivery of the active agent is via peripheral, parenteral administration, which as used herein refers to the injection of a dosage form into the body by a sterile syringe or some other mechanical device such as an infusionpump. Suitable peripheral parenteral routes include intravenous, intramuscular, subcutaneous, and intraperitoneal routes of administration. Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions(e.g., a vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection or Lactated Ringer's Injection, which may contain anti-oxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, preservatives, buffers, antioxidants, or other additives (e.g., wetting oremulsifying agents) known to those of skill in the art. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Agents of the present invention may also be administered topically or nasally.

The amount of agents of the present invention will depend upon the nature and severity of the diabetic condition being treated, the nature of prior treatments which the patient has undergone, and on a variety of other factors, including the typeof injury, the age, weight, sex, medical condition of the patient. Ultimately, the attending physician will decide the amount of the agent with which to treat each individual patient. Initially, the attending physician may administer low doses of agentand observe the patient's response. Larger doses of agent may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further.

Guidance on methods of determining dosages can be found in standard references, for example, Spilker, Guide to Clinical Studies and Developing Protocols, Raven Press Books, Ltd., New York, 1984, pp. 7-13 and 54-60; Spilker, Guide to ClinicalTrials, Raven Press, Ltd., New York, 1991, pp. 93-101; Craig et al., Modern Pharmacology, 2d ed., Little Brown and Co., Boston, 1986, pp. 127-133; Speight, Avery's Drug Treatment Principles and Practices of Clinical Pharmacology and Therapeutics, 3ded., Williams and Wilkins, Baltimore, 1987, pp. 50-56; Tallarida et al., Principles in General Pharmacology, Springer-Verlag, New York, 1998, pp. 18-20; and Olson, Clinical Pharmacology Made Ridiculously Simple, MedMaster, Inc., Miami, 1993, pp. 1-5.

More specifically, for example, A typical dosage range for GLP-1 and analogs and derivatives is about 1 pg/kg-1 mg/kg body weight, although these are approximations depending upon a large number of factors including the potency of the analog,its circulating half-life, the individual characteristics of the subject, and the like. Optimization of administration of insulin for diabetic treatment of individuals is well established, and similar optimization protocols are employed here. Forpurposes of illustration, in some embodiments, amounts of native GLP-1 range from about 0.03 to about 100 nmol/kg, and GLP-1 is administered via injection or by subcutaneous infusion, e.g., at a dose of 4.8 pmol/kg/min using a portable pump.

Doses of exendins for achieving enhancement of diabetes resolution will typically be in the range of about 10 to 30 .mu.g to about 5 mg/day, preferably about 10 to 30 .mu.g to about 2 mg/day and more preferably about 10 to 100 .mu.g to about 1mg/day, most preferably about 30 .mu.g to about 500 .mu.g/day, for a 70 kg patient, administered in a single or divided doses. By way of illustration, exendin-4 (commercially available from Amylin and Eli Lilly & Co. under the name BYETTA, and as ageneric version known as exenatide) is usually administered subcutaneously, in amounts ranging from about 5 to about 30 micrograms per day, and in some embodiments, is administered starting with 10 micrograms per day in two divided doses, and thenincreased e.g., after about one month, as required e.g., to 20 micrograms per day, and even up to about 30 micrograms or more per day, for at least e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more additional months. Thus, in some embodiments, theindividual formulation, e.g., for oral administration, contains about 5, 10 or 15 micrograms (corresponding to a divided daily total dose of 10, 20 or 30 micrograms).

For example, in some embodiments, GIP (1-42) (SEQ ID NO: 21) is administered by subcutaneous infusion in dosages ranging from about 0.1 to about 10 pmol/kg/min (e.g., about (1-4 pmol/kg/min) or by bolus injection ranging from about 6.25 to about25 nmol/kg/day. By way of additional example, in some other embodiments, GIP or GIP analogue is administered subcutaneously in dosages ranging from about 6.25 to about 25 nmol/kg/day, wherein if required, the dosage is increased over the treatmentperiod or a portion thereof, e.g., with initial dosages of about 6.25 nmol/kg/day and a maximum of about 25 nmol/kg/day.

DPP IV inhibitors may be administered at an initial dosage of about 100 mg/day. The dosage may be increased if necessary, with a maximum of about 200 mg/day.

Individual patients will have varying responses to treatments with the gastrointestinal hormones described herein. Clinicians skilled in the art will therefore appreciate that for some patients a combination of the therapies will be moreeffective than any single therapy alone. Patient clinical and/or biochemical characteristics will guide clinicians in choosing combination therapies to achieve diabetes resolution after gastric restriction surgery. Representative combinations ofhormones suitable for use in the present invention may include GIP and GLP-1; and GLP-1 and the DPP IV inhibitor sitagliptin.

Diabetic resolution is judged to have occurred when evidence of normal glucose metabolism is present. This includes, but is not limited to: a fasting glucose below about 125 mg/dL, hbA1c below about 7%, fasting insulin above about 7microunits/ml, fasting c-peptide above about 0.4 ng/ml, and a 2 hour post glucose loading c-peptide above about 2.0 ng/ml. These values may have an uncertainty value of +/-5%.

Once diabetes resolution has occurred, therapy with GLP-1 or analog is discontinued. At this point, the patient is encouraged to continue home fasting and glucose monitoring for 30 days. If the fasting glucose remains below 125, the patient isconsidered to be non-diabetic. Home glucose monitoring is then discontinued.

Embodiments of the present invention are now described in connection with the following non-limiting examples.

EXAMPLES

The first example is that of a 63 year old, morbidly obese Caucasian male, with type II diabetes for many years. He weighed 331 pounds and had a body mass index of 44. His preoperative medications included repaglinide and metformin. Thepatient underwent laproscopic gastric restriction surgery. He was placed on a low calorie, high protein, bariatric diet and encouraged to exercise regularly. However, he remained diabetic despite experiencing a 56-pound weight loss. He was started onexenatide and instructed to discontinue his prior diabetic medications. The initial dosage was 10 mcg daily which was advanced to 20 mcg after one month.

He lost an additional 44 pounds during the 13 months on exenatide. This was much more than would have been expected by gastric restriction surgery alone. His fasting glucose was 95 with post prandial glucoses below 150. He was instructed todiscontinue exenatide. He continued home fasting glucose monitoring for 30 days. The fasting glucose remained below 125. Home glucose monitoring was then discontinued. He continued routine follow care. His diabetes was considered to have beenresolved.

The second example is that of a 51-year old, morbidly obese Caucasian male, with type II diabetes for many years. He weighed 348 pounds and had a body mass index of 50. His preoperative medications included metformin. The patient underwentlaparoscopic gastric restriction surgery. He was placed on a low calorie, high protein, bariatric diet and encouraged to exercise regularly. However, after 3 months he had experienced only a modest weight loss of 15 pounds and remained diabetic. Hewas started on exenatide and instructed to discontinue his prior diabetic medications. The initial dosage was 10 mcg daily which was advanced to 20 mcg after one month.

He lost an additional 51 pounds during the 7 months on exenatide. This was much more than had been expected by gastric restriction surgery alone. His fasting glucose was 95 with post prandial glucoses below 150. He was instructed todiscontinue exenatide. He continued home fasting glucose monitoring for 30 days. The fasting glucose remained below 125. Home glucose monitoring was then discontinued. He continued routine follow care. His diabetes was considered to have beenresolved.

The third example is that of a 71-year old, morbidly obese Caucasian female, with type II diabetes for many years. She weighed 315 pounds and had a body mass index of 55.8. Her preoperative medications included glimipride, nateglinide andmetformin. The patient underwent laparoscopic gastric restriction surgery. She was placed on a low calorie, high protein, bariatric diet and encouraged to exercise regularly. However, after 3 months she had experienced only a modest weight loss of 21pounds and remained diabetic. She was started on exenatide. She discontinued her prior diabetic medications after one month. The initial dosage of exenatide was 10 mcg daily which was advanced to 20 mcg after one month.

She lost an additional 53 pounds during the 7 months on exenatide. This was much more than the amount that would have been expected by gastric restriction surgery alone. Her fasting glucose and post prandial glucoses were below 110. Her HbA1Cwas <6%. Her diabetes was considered to have been resolved.

The fourth example is that of a 55-year old, morbidly obese Caucasian female, with recently diagnosed with type II diabetes. She weighed 252 pounds and had a body mass index of 40. She was not on preoperative diabetic medications. The patientunderwent laparoscopic gastric restriction surgery. She was placed on a low calorie, high protein, bariatric diet and encouraged to exercise regularly. She was started on exenatide postoperatively. The initial dosage was 10 mcg daily which wasadvanced to 20 mcg after one month.

She lost 96 pounds during the 7 months on exenatide. This was much more than the amount that would have been expected by gastric restriction surgery alone. Her fasting glucose and post prandial glucoses were below 110. Her HbA1C was <6%. Her diabetes was considered to have been resolved.

INDUSTRIAL APPLICABILITY

The present invention has applicability in clinical medicine and therapeutics, and more specifically for example in the treatment of obese diabetics.

All patent and non-patent publications cited in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All these publications and patent applications are herein incorporated byreference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to beunderstood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims.

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57omo sapiensN-term H p Glu Phe Glu Arg His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu 2 Val Lys Gly Arg Gly 35 23o sapiensC-term amide 2His Ala GluGly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg 2 33ificial SequenceDescription of Artificial Sequence Synthetic polypeptide 3His Ala Glu Gly Thr Phe Thr Ser Asp Val SerSer Tyr Leu Glu Gly Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 2 428PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 4His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys 29PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 5His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Lys Glu Phe Ile Ala Trp LeuVal Lys Gly 2ificial SequenceDescription of Artificial Sequence Synthetic polypeptide 6His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg 273ificial SequenceDescription of Artificial Sequence Synthetic polypeptide 7His Val Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 2 83ificialSequenceDescription of Artificial Sequence Synthetic polypeptide 8His Ala Gln Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 2 93ificial SequenceDescription ofArtificial Sequence Synthetic polypeptide 9His Ala Glu Gly Thr Phe Thr Ser Asp Thr Ser Lys Tyr Leu Glu Gly Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 2 Artificial SequenceDescription of Artificial SequenceSynthetic polypeptide la Glu Gly Thr Phe Thr Ser Asp Val Ser Lys Tyr Leu Glu Gly Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 2 Artificial SequenceDescription of Artificial Sequence Synthetic polypeptidela Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg 2 Heloderma horridum er Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 2 Ser Gly Ala Pro Pro Pro Ser 35 Heloderma suspectum ly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer 2 Ser Gly Ala Pro Pro Pro Ser 35 Artificial SequenceDescription of Artificial Sequence Synthetic polypeptide ly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn GlyGly 2 Artificial SequenceDescription of Artificial Sequence Synthetic polypeptide ly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly 2 ArtificialSequenceDescription of Artificial Sequence Synthetic peptide ly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn 239PRTArtificial SequenceDescription of Artificial SequenceSynthetic peptide ly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser 2 Ser Gly Ala Pro Pro Pro Ser 35 Artificial SequenceDescription of ArtificialSequence Synthetic peptide ly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn 228PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide ly Glu GlyThr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Ala Val Arg Leu Ala Ile Glu Phe Leu Lys Asn 23ificial SequenceDescription of Artificial Sequence Synthetic polypeptide 2a Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr LeuGlu Gly Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Arg Gly Arg Gly 2 2rtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 2a Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys HisGln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys Asn Asp Trp Lys His Asn Ile Thr Gln 35 4RTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 22Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile 23tificial SequenceDescription of Artificial Sequence Synthetic peptide 23Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala 24tificial SequenceDescription of Artificial Sequence Synthetic peptide 24Tyr Ala Glu Gly Thr Phe Ile SerAsp Tyr Ser Ile Ala Met 25tificial SequenceDescription of Artificial Sequence Synthetic peptide 25Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp PRTArtificial SequenceDescription of Artificial Sequence Syntheticpeptide 26Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 27Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 28tificial SequenceDescription of Artificial Sequence Synthetic peptide 28Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His 29tificial SequenceDescription of Artificial Sequence Synthetic peptide 29Tyr AlaGlu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln 3rtificial SequenceDescription of Artificial Sequence Synthetic peptide 3a Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln 2RTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 3a Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp 2RTArtificial SequenceDescription of Artificial Sequence Syntheticpeptide 32Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe 2RTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 33Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met AspLys His Gln Gln Asp Phe Val 2RTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 34Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn 2RTArtificialSequenceDescription of Artificial Sequence Synthetic peptide 35Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp 226PRTArtificial SequenceDescription of Artificial Sequence Syntheticpeptide 36Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu 227PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 37Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr SerIle Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu 228PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 38Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln AspPhe Val Asn Trp Leu Leu Ala 229PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 39Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln 23ificial SequenceDescription of Artificial Sequence Synthetic polypeptide 4a Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys 2 4rtificialSequenceDescription of Artificial Sequence Synthetic polypeptide 4a Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly 2 4232PRTArtificial SequenceDescription ofArtificial Sequence Synthetic polypeptide 42Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 4333PRTArtificial SequenceDescription of Artificial SequenceSynthetic polypeptide 43Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys 4434PRTArtificial SequenceDescription of Artificial Sequence Syntheticpolypeptide 44Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys Asn 4535PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide45Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys Asn Asp 35 4636PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 46TyrAla Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys Asn Asp Trp 35 4737PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 47Tyr AlaGlu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys Asn Asp Trp Lys 35 4838PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 48Tyr AlaGlu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys Asn Asp Trp Lys His 35 4939PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 49TyrAla Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys Asn Asp Trp Lys His Asn 35 5rtificial SequenceDescription of Artificial Sequence Syntheticpolypeptide 5a Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys Asn Asp Trp Lys His Asn Ile 35 4RTArtificial SequenceDescription of ArtificialSequence Synthetic polypeptide 5a Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys Asn Asp Trp Lys His Asn Ile Thr 35 4RTArtificialSequenceDescription of Artificial Sequence Synthetic polypeptide 52Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys Asn Asp Trp Lys His Asn Ile Thr Gln35 4RTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 53Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys 2 Lys Asn Asp TrpLys His Asn Ile Thr Gln 35 4RTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 54Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys2 Lys Asn Asp Trp Lys His Asn Ile Thr Gln 35 4RTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 55Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys His Gln Gln Asp Phe Val Asn Trp LeuLeu Ala Gln Lys Gly Lys 2 Lys Asn Asp Trp Lys His Asn Ile Thr Gln 35 4RTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 56Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys Ile His Gln Gln Asp Phe Asn Trp Leu LeuAla Gln Lys 2RTArtificial SequenceDescription of Artificial Sequence Synthetic

polypeptide 57His Ala Gln Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 2

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